Murine METS Protein Signaling
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Murine METS Protein Signaling

The macrophage differentiation system in mouse establishes the fact that, the macrophages stop proliferate during the process of cell differentiation. Induction of METS (Mitogenic Ets Transcriptional Suppressor METS) otherwise known as Ets (E26 Avian Leukemia Oncogene) repressor, leads to terminal differentiation and cell cycle arrest. Inside macrophages, METS blocks HRas1 (Harvey Rat Sarcoma Virus Oncogene-1)-dependent proliferation without inhibiting HRas1-dependent expression of cell type-specific genes by selectively replacing Ets activators on the promoters of cell cycle control genes. Anti-proliferative effects of METS require its interaction with Ddx20 (DEAD (Asp-Glu-Ala-Asp) Box Polypeptide-20) that assembles a novel co-repressor complex (Ref.1 & 2). The transcriptional repression involving METS with Ddx20 is selective and does not involve all Ets regulated genes. While cell cycle genes are repressed by METS, other gene activated by Ets factors such as those involved in differentiation are not repressed by METS. The transcriptional repression by METS also involves members of the Rb (Retinoblastoma) family of tumor suppressors, such as Rb, p107 and p130. METS and Ddx20 interaction suppress functioning of the cell cycle gene, E2F4 (E2F Transcription Factor-4); proteins like HDAC2 and HDAC5; NCOR2 (Nuclear Receptor Co-Repressor-2) and Sin3A (Transcriptional Regulator Sin3A (Yeast)) and Sin3B (Transcriptional Regulator Sin3B (Yeast)). METS is assumed to be regulated by serine phosphorylation but experimental data showing this regulation is still lacking (Ref.3).

HRas1 signaling initiated by M-CSF (Macrophage Colony Stimulating Factor) through CSF1R (Colony-Stimulating Factor-1 Receptor) leads to transcriptional activation of a large set of target genes by a mechanism that depends on cooperative interactions between Ets factors (Ets1 (E26 Avian Leukemia Oncogene 1, 5 Domain) and Ets2 (E26 Avian Leukemia Oncogene 2, 3 Domain)) and members of the Activator Protein-1 family of transcription factors (Jun (Jun oncogene)/c-Jun and Fos (FBJ Osteosarcoma Oncogene)/c-Fos) (Ref.3). While METS exhibits an overlapping DNA binding specificity with Ets2 and other Ets activators, it does not inhibit transcription of macrophage-specific genes that are activated by Activator Protein-1/Ets ternary complexes. METS selectively represses Ets target genes involved in Ras (a membrane associated Guanine nucleotide-binding protein)-dependent proliferation while sparing genes that are targets of Ras-dependent differentiation (Ref.2 & 4).